Oral alveolar bone loss is commonly caused by periodontal and periapical diseases associated with bacterial infection. At the initial stage of host defense, immune cells produce a variety of immune cytokines to fight against the bacterial infection. Under physiological condition, bone resorption is delicately balanced and coupled with bone extracellular matrix deposition or bone formation, ensuring that new bone is generated where old bone is removed. However, the persistent immune response in periodontal and periapical diseases disrupts the balance between bone formation and bone resorption, resulting in alveolar bone destruction and tooth loss. Currently while there is a good understanding of how immune cells and the cytokines they secret stimulate oral bone resorption, the underlying mechanism by which oral bone formation is inhibited in oral osteoimmune responses remains a mystery. Our preliminary studies revealed that immune cytokines activate I:B kinase (IKK) to inhibit osteoblast differentiation. Using two lines of transgenic mice which specifically expressed the IKK inhibitors in osteoblasts, we discovered that IKK activation by immune cytokines potently impaired bone forming function of differentiated/mature osteoblasts in osteoporotic immune bone loss. Based on these exciting findings, we hypothesize that the activation of IKK by immune cytokines in osteoblasts mediates the uncoupling of bone formation from bone resorption in oral immune bone loss. To fully understand the molecular mechanisms of alveolar bone loss due to infection, we propose the following four specific aims. Specific Aim 1 is to examine whether immune cytokines inhibit oral osteogenesis by activating IKK in vitro. Specific Aim 2 is to determine whether IKK activation plays a critical role in oral inflammatory bone loss in vivo by inhibiting bone formation. Specific Aim 3 is to determine whether the inhibition of IKK activation attenuates oral bone loss by maintaining osteoblast function under an osteoporotic condition in vivo. Specific Aim 4 is to explore the molecular mechanisms by which immune cytokines mediate the uncoupling of bone formation from bone resorption through IKK in osteoimmune responses. In summary, these studies will provide new insights into the osteoimmune mechanisms of oral bone loss, and may have important implications in the treatment of oral and systemic bone disorders. Project Narrative: Gum disease and dental pulpal infection often cause soft tissue and oral alveolar bone destruction, resulting in tooth loss. At the initial stage of host defense, immune cells such as lymphocytes and macrophages produce a variety of inflammatory mediators to fight against bacterial infection. Due to the open environment of the oral cavity, oral immune responses are not easily resolved and frequently cause alveolar bone loss. It has been known for a long time that inflammatory mediators not only stimulate oral bone resorption, but also inhibit oral bone formation. While there is a good understanding of how oral bone resorption is triggered, the underlying mechanisms by which oral bone formation is suppressed remain a mystery in oral inflammation. Our preliminary studies suggest that the activation of I:B kinase (IKK) by inflammatory mediators may play a critical role in the inhibition of oral bone formation. To fully understand the molecular mechanisms of alveolar bone loss due to infection, we will examine whether the inhibition of IKK abolishes inflammatory mediator-mediated inhibition of oral osteogenesis. We will determine whether the inhibition of IKK prevents oral bone loss induced by the dental pulpal infection by maintaining osteoblast functions. Finally, we will explore how IKK suppresses oral bone formation by inducing gene expression. In summary, these studies will provide new insights into the molecular mechanisms of oral bone loss due to infection, and may have important implications in the treatment of oral and systemic bone disorders.